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Lactic acidosis: Metformin hydrochloride: Lactic acidosis is a very rare, but serious and potentially fatal in the absence of prompt treatment, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, dehydration, any acute conditions associated with hypoxia or impacting renal function (see Precautions).
Medicinal products that can acutely impair renal function, such as antihypertensives, diuretics and NSAIDs, should be initiated with caution in metformin-treated patients (see also Interactions).
Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterized by symptoms such as acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If lactic acidosis is suspected, treatment with XIGDUO XR should be discontinued and the patient hospitalized immediately.
Use in patients with renal impairment: XIGDUO XR is not recommended for the treatment of diabetes in patients with eGFR persistently below 45 mL/min/1.73 m2 as the glycemic efficacy of dapagliflozin is dependent on renal function (see Dosage & Administration). The maximum dose of metformin in patients with an eGFR of 30 to less than 45 mL/min/1.73 m2 is 1000 mg once daily.
Due to metformin, XIGDUO XR is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see Contraindications).
Dapagliflozin has not been studied in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) by MDRD or end-stage renal disease (ESRD).
Metformin is excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function (see Precautions).
Assess renal function prior to initiation of XIGDUO XR and then periodically thereafter: at least annually; at least two to four times a year in patients with renal function where eGFR levels are approaching 45 mL/min/1.73 m2 and in elderly patients.
Use in patients with hepatic impairment: Dapagliflozin: There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment. Dapagliflozin should not be used in patients with severe hepatic impairment (see Dosage & Administration and Pharmacology under Actions).
Metformin hydrochloride: Since impaired hepatic function has been associated with some cases of metformin-associated lactic acidosis, XIGDUO XR should be avoided in patients with clinical or laboratory evidence of hepatic disease.
Acute conditions associated with hypoxia or impacting renal function: Metformin hydrochloride: Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. Acute conditions such as dehydration, severe infections, and hypoperfusion, have potential to alter renal function. In these situations, metformin must be discontinued.
Radiologic studies with intravascular iodinated contrast materials: Metformin hydrochloride: Intravascular administration of iodinated contrast agents in radiological studies can lead to an acute decrease in renal function and has been associated with lactic acidosis in patients receiving metformin. XIGDUO XR should temporarily be discontinued prior to, or at the time of the procedure, and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be stable.
Surgical procedures: Metformin hydrochloride: Metformin must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.
Excessive Alcohol intake: Metformin hydrochloride: Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving XIGDUO XR.
Ketoacidosis: Dapagliflozin: There have been reports of ketoacidosis, including diabetic ketoacidosis, in patients with type 1 and type 2 diabetes mellitus taking dapagliflozin and other SGLT2 inhibitors. XIGDUO XR is not indicated for the treatment of patients with type 1 diabetes mellitus.
Patients treated with XIGDUO XR who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, discontinuation or temporary interruption of XIGDUO XR should be considered and the patient should be promptly evaluated.
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from pancreatic disorders (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, illness or surgery and alcohol abuse. XIGDUO XR should be used with caution in these patients.
Treatment should be interrupted in patients who are hospitalized for major surgical procedures or acute serious medical illnesses.
Consider monitoring for ketoacidosis and temporarily discontinuing XIGDUO XR in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting XIGDUO XR.
Change in clinical status of patients with previously controlled type 2 diabetes: A patient with type 2 diabetes previously well-controlled on XIGDUO XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, XIGDUO XR must be stopped immediately and other appropriate corrective measures initiated.
Vitamin B12 decrease/deficiency: Metformin hydrochloride: Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contraindicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.
Use in patients at risk for volume depletion: Dapagliflozin: Due to its mechanism of action, dapagliflozin induces osmotic diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacology: Pharmacodynamics under Actions).
For patients at risk for volume depletion due to co-existing conditions, a starting dose of dapagliflozin 5 mg once daily may be appropriate as XIGDUO XR or individual components.
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
For patients receiving dapagliflozin, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended.
Temporary interruption of XIGDUO XR should be considered for patients who develop volume depletion.
Use with medications known to cause hypoglycemia: Dapagliflozin: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with dapagliflozin (see Pharmacology: Pharmacodynamics under Actions).
Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.
Necrotising fasciitis of the perineum (Fournier's gangrene): Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier's gangrene), have been reported in female and male patients taking SGLT2 inhibitors (see Adverse Reactions). This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.
Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotizing fasciitis. If Fournier's gangrene is suspected, XIGDUO XR should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
